People infected with HIV can expect a near normal life on antiretroviral therapy. In the United States, cancer has become the leading cause of death in the aging HIV-positive population. This includes, even to date, the AIDS-defining cancers Kaposi sarcoma (KS) and lymphoma, such as primary effusion lymphoma. For AIDS-associated cancers like KS and PEL, no new therapies have been developed since the late 1990s. We, and others have shown that KS and AIDS-associated lymphomas are highly dependent on the PI3K/Akt/mTOR signaling pathway for survival and oncogenesis. The PI3K/Akt/mTOR signaling pathway is activated in many cancers. The mammalian target of rapamycin (mTOR) is a serine/threonine kinase that is a downstream target of the PI3K and Akt kinases. Mechanistically, the activated mTOR-raptor complex (mTORC1) phosphorylates S6 kinase (p70S6K) and 4E binding protein (4E-BP1). Inhibitors of mTOR, primarily rapamycin and its newer derivatives are currently being evaluated as therapeutics against many cancers. We conducted the first clinical trial of rapamycin in the context of HIV infection. This uncovered evidence of clinical efficacy though the mechanism is unclear. We propose to determine the molecular mechanisms by which mTOR inhibition induces regression of HIV-associated cancers in vitro and in vivo. We also propose to explore the efficacy of dual inhibition of PI3K/Akt and mTOR using rapamycin in combination with other inhibitors targeting other components in this pathway, as well as single agent dual PI3K/mTOR inhibitors eg. NVP-BEZ235 against AIDS-associated KS and lymphomas. Thus, in this application, we propose to investigate the PI3K/Akt/mTOR pathway in KS and PEL, as a model of HIV-associated cancers that are critically dependent on this pathway for their survival. We propose to identify drug combinations and to delineate the molecular mechanism of these therapeutics, which will serve as the next generation of therapies against KS and lymphoma in the context of HIV infection. Since PI3K/Akt kinases have also been shown to be required for optimal HIV infection and replication, we will also test these therapies against HIV replication. Importantly, we are not working with tool compounds, but we only propose to work with drugs that have passed human phase I safety trials and thus will be immediately available for clinical trials for HIV- associated KS and lymphomas. PUBLIC HEALTH RELEVANCE: This is an application to understand the mechanism of mTOR inhibitors in AIDS-associated cancers, specifically Kaposi Sarcoma and HIV/AIDS lymphomas. It is based on the clinical success of mTOR inhibitors in sarcoma, which at the same time uncovered limitations of single agents. This application will understand the KS-specific mechanism of action and explore novel combination therapy approaches.